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This retrospective cohort study evaluated the efficacy and safety of furmonertinib in managing central nervous system (CNS) metastases among NSCLC patients with uncommon EGFR mutations (excluding exon 20 insertion variants). Thirty\u2010one eligible patients treated at the Affiliated Brain Hospital of Nanjing Medical University between March 2022 and August 2024 were enrolled. Serial cerebrospinal fluid (CSF) samples were subjected to next\u2010generation sequencing for circulating tumor DNA (ctDNA) profiling. Clinical endpoints included CNS objective response rate (ORR), disease control rate (DCR), intracranial progression\u2010free survival (iPFS), overall survival (OS), and safety parameters. The cohort demonstrated a CNS ORR of 38.7% (95% CI, 21.8%\u201357.8%) and DCR of 64.5% (95% CI, 45.4%\u201380.8%), with a median iPFS of 6.97\u2009months. Median OS remained immature at data cutoff. A total of 21 patients with leptomeningeal metastases had baseline EGFR\u2010mutant ctDNA detected in their CSF, with ctDNA analysis indicating intracranial responses corresponded to decreased or cleared ctDNA abundance. Longitudinal CSF ctDNA monitoring in a representative case demonstrated significant temporal correlation between molecular response and radiographic\/clinical improvement. The safety profile was favorable, with no grade\u2009\u22654 adverse events or treatment\u2010related mortality. These findings suggest that furmonertinib provides clinically meaningful CNS activity with acceptable toxicity in uncommon EGFR\u2010mutant NSCLC, particularly when integrated with CSF ctDNA dynamics as a potential pharmacodynamic biomarker. This study highlights the therapeutic implications of third\u2010generation EGFR\u2010TKIs in molecularly defined NSCLC subpopulations.<\/jats:p>","DOI":"10.1002\/ijc.35460","type":"journal-article","created":{"date-parts":[[2025,4,29]],"date-time":"2025-04-29T08:49:54Z","timestamp":1745916594000},"page":"954-963","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":7,"title":["Furmonertinib in uncommon <scp>EGFR<\/scp>\u2010mutated non\u2010small cell lung cancer with central nervous system metastases: A retrospective cohort study"],"prefix":"10.1002","volume":"157","author":[{"given":"Yuwen","family":"Xie","sequence":"first","affiliation":[{"name":"Brain Metastases Diagnosis and Treatment Centre The Affiliated Brain Hospital of Nanjing Medical University  Nanjing China"},{"name":"Department of Respiratory Medicine Nanjing Chest Hospital, The Affiliated Brain Hospital of Nanjing Medical University  Nanjing 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